2,13-dimethyl-2-formyl-7-hydroxypolyhydrophenanthrene-1-acetic acids and production thereof



United States P 2,13-DIMETHYL- 2 -FORMYL 7 HYDROXYPOLY-HYDROPHENANTHRENE-l-ACETIC ACIDS AND PRODUCTION THEREOF Max N. Huffman,Oklahoma City, Okla., assignor to G. D. Searle & Co., Chicago, Ill., acorporation of Illinois No Drawing. Original application July 12, 1949,Serial No. 104,378, now Patent No. 2,615,041, dated October 21, 1952.Divided and this application January 25, 1952, Serial No. 268,349

6 Claims. (Cl. 260-514) This invention relates to the manufacture ofpolyhydrophenanthrene derivatives from correspondingcyclopentanopolyhydrophenanthrene compounds. It is an object of thisinvention to produce and to provide a method for producing apolyhydrophenanthrene derivative having a CHO group on one of the C1 andC2 positions and a CHz-COOH on the other from a correspondingcyclopentanopolyhydrophenanthrene compound having a ketone group on oneof the C16 and C17 positions and a hydroxyl group on the other.

More specifically, it is an object to produce and to provide a methodfor producing a polyhydrophenanthrene derivative having a CHz-COOH groupon C1 and a CHO group on C2 from a cyclopentanopolyhydrophenanthrenecompound having a ketone group on C16 and a hydroxyl group on C17.

Another object is to produce and to provide a method for producing froma steroid of the estrogen and androgen series of compounds having aketone group on C16, and a hydroxyl group on C17, apolyhydrophenanthrene having a CHO group on C2 and a CHz-COOH group onC1 in quantitative yield without side reaction and without altering thenuclear structure of the phenanthrene ring.

A further object is to produce marrianolic acid hemi aldehyde (tertiary)having a hydroxyl or substituted ether or ester group on C7 from anestrogen compound having a ketone group on C16 and a hydroxyl group onC17,Cand a hydroxyl or substituted ether or ester group on 3.

A still further object is to provide a method for isolating thedescribed polyhydrophenanthrene derivative as a relatively pure compoundfrom the product of the reaction of the correspondingcyclopentanopolyhydrophenanthrene from which it is derived.

This application is a division of my copending application Serial No.104,378, filed July 12, 1949, now Patent No. 2,615,041.

Compounds of the type produced by my invention may be used as chemicalintermediates in the production of phenanthrene andcyclopentanopolyhydrophenanthrene derivatives; thev have physiologicalactivity and may be used to supplement the hormone production of thebody; they provide for new arrangements favoring their entrance into thenormal metabolic reactions of the human body in a manner to make up thedeficiencies or to cause body reactions for the cure or prevention ofdisease and sickness.

It has been found that polyhydrophenanthrene compounds having a CHOgroup on C2 and a CH2-CO()H group on C1 can be prepared of acorresponding cyclopentanopolyhydrophenanthrene derivative having aketone group on C16 and a hydroxyl group on C17 by reaction of theparent compound with a substance capable of degradative oxidation tosplit the carbon-carbon bond between C16 and C17 and to form, as theoxidative reaction product, a polyhydrophenanthrene having the samenuclear construction as the parent compound, a

this invention may be described as a2-aldo-polyhydrophenanthryl-l-acetic acid corresponding to the formula,

2,699,447 Patented Jan. 11, 1955 ICC where R is an oxygen containinggroup, such as carbonyl (=0), hydroxyl (OH), ether (OR') or ester (OOCR)in which R is a monovalent organic radical of the type aliphatic,aromatic, mixed aliphatic-aromatic, such as methyl, ethyl, propyl,butyl, penty'l, stearyl, benzyl, phenyl, and the like, Rz may be absentor it may be methyl as in the estrogen and androgen series of compounds,R may be absent as in the estrogen series of compounds, or it may bemethyl as in the androgen series of compounds. Rings A, B and C may becompletely saturated, or rings A, B and C singly or in variouscombinations may have one or more unsaturated groups. For example, ringA may have three unsaturated groups to comprise a benzenoid structure,as in compounds derived from estrone, rings A and B may both bebenzenoid, as in compounds derived from equilenin, or ring A may beunsaturated at A as in compounds derived from testosterone, or all threeof the rings A, B and C may be benzenoid.

The parent compound is selected of a cyclopentanopolyhydrophenanthrenehaving the same nuclear construction as the desiredpolyhydrophenanthrene derivative and is constituted with a ketone groupon C16 and a hydroxyl group on CW The C3 position of the parent compoundmay be ketonic, hydroxyl, or it may comprise an ester or ether. If thehydroxyl at C3 is subject to oxidative attack by the reagents used toeffect the degradative oxidation reaction, it is desirable to protectthe C3 position by esterification or etherification. The protector groupmay subsequently be reconverted to hydroxyl, when desired, by suitablereaction, such as hydrolysis following saponification or by reactionwith hydriodic or hydrobromic acid. It is not always essential, in fact,it is not desirable to replace the hydroxyl group when it is notphenolic. Suitable parent compounds of the estrogen series and methodsfor manufacturing others are described in my copending applicationSerial No. 1258, filed on January 7, 1948, now Patent No. 2,522,-

As the compound for effecting degradative oxidation quantitatively andwithout undesirable side reactions I prefer to use a lead tetra-acylate,such as lead tetraacetate, lead tetra-propionate, lead tetra-butyrate,or a lead tetra-arylate, such as lead tetra-benzoate, leadtetraphenylate, and the like. The desired reactivity is secured when theparent compound and the compound capable of degradative oxidation arepresent in equi-molecular proportions. However, I prefer, and I believebest results are secured, When an excess of the degradative oxidant inamounts ranging up to about 10 or 20 per cent is used. Reaction withlead tetra-acetate or other acylates, including arylates, is bestcarried out in solvent medium in which the acylate is soluble. Suitablesolvent systems include acetic acid (glacial) or other carboxylic acid,preferably having an acyl radical which corresponds to the acyl group ofthe reaction compound. Reaction may also be carried out in other solventsystems in which acetic acid may be wholly or partially replaced byinert solvents of the type benzene, chloroform, nitrobenzene,dichlorethane, tetrachlorethane, and the like. Desirable reaction issecured only when water or alcohols are present in the system, and forthis purpose it is expedient to add small amounts of Water to thesolvent system. Reaction may be carried out at or below room temperaturein reasonable time which at room temperature may extend to about 24hours, and it may be carried out more rapidly at elevated temperaturesbelow the boiling point for the solvent and preferably below C. Insteadof using an organic solvent system the reaction may be carried out inaqueous medium if the rate of oxidative cleavage exceeds the velocity ofhydrolysis of the lead tetra-acylate.

Although exact equivalency is not apparent, degradative oxidation of thesame character may be secured by the use of periodates instead of leadtetra-acylates. The term periodates may be taken as including periodicacid, paraperiodic acid, water-soluble salts of periodic acid andparaperiodio acid in which the metal component is selected of the alkalimetals, such as sodium, potassium, and including ammonium or a metal ofthe type barium. For example, it may be sodium perio'date, sodiummetaperiodate, trisodium paraperiodate, and the like. Ordinarily, thereaction with periodates is carried out in aqueous medium at or belowroom temperatures with equi-molecular proportions of the reactants orslight excesses of the periodates ranging up to to per cent.Alternately, water may be partially replaced withacetic acid or otherlike carboxylic acids, dioxane, methanol or other low boiling alcohols,or mixtures of ethanol or. alcohols with ethyl acetate. Reaction mayalso be carried out atelevated temperatures limited by the boiling pointof the solvent but preferably below 100 C.

According to the present process, the parent compound (I), treated withthe degradative oxidant, such as lead tetra-acetate, causes splitting ofthe carbon-carbon bond between Cisand C17, (II), and by oxidativereaction forms a CHO group on C2 and CH2COOH group on C1, (III). Whenthe described conditions are met, the reaction proceeds smoothly andquantitatively without disturbing the double bonds of the nucleus, thegroups substituted thereon, and without side reactions. In the eventthat the C3 position of the parent compound is phenolic, it is best tosubstitute a group which is unaffected by the oxidation reaction, andfor this purpose it is best to substitute an ester or other group whichis easily and smoothly reconvertible to hydroxyl when desired.Reconversion may be made by the ordinary methods of hydrolysis,saponification or like treatment.

Isolation of the desired oxidative reaction product may be achieved bycrystallization at reduced temperature. For best results, it isdesirable to dilute the reaction prodnot with water or water containinga small amount (1 to 20 percent) alcohol or polyhydric alcohol, such asmethanol, ethanol, ethylene glycol, diethylene glycol, propylene glycol,triethylene glycol, and the like. Purification may be may be carried outby recrystallization from dilutions with Water which may have smallamounts .of methanol or polyhydric alcohol of the types described.Isolation may also be carried out by extraction from aqueous medium withether, or other immiscible solvent in which the derivative is soluble,such as ethyl ether, followed by evaporation of the ethereal phase todeposit the desired oxidative reaction product. Generally the etherealphase is washed one or two times with water, an evaporation preferablyis carried out at reduced atmosphere.

There is reason to believe that similar reaction takes place when theC17 position of the parent compound is ketone and the C16 position ishydroxyl to produce as the degradative oxidation reaction product thecorresponding polyhydrophenanthrene derivative having a CHO group on C1and CH2''COOH group on C2;

By way of illustration but not by way of limitation, the followingexamples of my invention are given. Amounts of materials are given ingrams (g.), milligrams (mg), and cubic centimeters (cc.), andtemperatures are recorded in degrees centigrade C.).

EXAMPLE 1 The preparation of mar'rianolz'c acid-hemialdehyde(te'rtiary)-7-methyl ether (V) Esterification to replace the hydroxylwhen present, on Ca may be effected by reaction with acetic acid to formthe corresponding 3-acetate. The hydroxyl group alternatively may bereplaced by an ether group in the manner of Butenandt, Stormer andWestphal, Z. Physio. Chem, 208 (1932). To 395 mg. oflfi-keto-a-estradiol- 3-methyl ether (IV) is added 23 cc. of 0.057 molarlead methods of decantation or filtration, and they may be furtherpurified" by a water washand then allowed to dry in air at roomtemperature. For further purification, the crystals may be dissolved inmethanol (15 cc.) at room temperature, to which..2. cc. of acetic acidmay be added, from which solution, the-end product is secured byreprecipitation'upon the addition of 200 cc. of water. The 3-alkoxygroup is-replaceable with hydroxyl by boiling in acetic acid-hydriodicacid.

The crystalline aldehyde acid melts at about 144.5- l'45i5 C. and itfurnishes a semi-'carbazone acid decomposingat about 185-186" C.'Esterification of this semicarbazone acid with diazomethane gives thesemi-carba- Zone methyl ester decomposing at 166-1675 C.

In the-above example. the acetic acid functions asa solvent for the leadtetra-acetate and it. also operates as a depressant to the oxidativespeed of the lead tetra-acetate. The acetic acid may be wholly orpartially replaced by dioxane, benzene or other organic solventspreviously described. Instead of the water added to the reactants, otherhydroxy compounds, such as alcohols, may be used. However, in theeventthat an alcohol is employed, the corresponding ester. of'thealdehydic-acid is obtained.

To 110" mg. of 'l6-keto-a-estradio1-3-benzoate (VII) is added 10 cc. of0.0294 molar lead tetra-acetate in acetic acid, andthe mixture isswirled at room temperature until complete solution of the steroid isefiected. Ten drops of water are added with mixing, and the mixture isallowed to stand at room temperature for about 60 hours in the absenceof light. The reaction mixture is then diluted with cc. of 1 per centethylene glycol in water and placed in a refrigerating atmosphere forreduction in temperature. After exposure for a period corresponding toabout 24 hours a'flocculent precipitate is thrown downwhich may beeasily filtered.

The aldehyde acid (VI givesan oxime melting at 183-185 C., and theproduct is soluble in sodium bicarbonate solution.

EXAMPLE 3 The preparation of 7-hydroxy-2-aldo-2,13-dimethyld0-decahydrophenanthryl-J-acetic acid (VIII) To 0.60 g. of A-androstene-3(fi)-17(a)-diol-16-one (VIIa) is added 30 cc. of 0.0723molar lead tetraacetate in acetic acid. The steroid dissolves almostimmediately at room temperature, and 6 cc. of 50 percent acetic is mixedin, The reaction solution is swirled continuously for 30 minutes andthen diluted with several volumes of water containing 2 cc. of ethyleneglycol (serves to expend the free lead tetra-acetate). After a few daysat reduced temperature, crystalline aldehyde acid (VIII) is precipitatedand separated from the liquids by filtratron. The crystalline productmay be further washed with water with or without small amounts ofalcohol to effect further purification.

CH3 OH OH: CH3 CH3 C D C -CH2C O OH A B A B HO HO VIIa VIII OH: OH

CoHs-CO VII CHl

OH2OO OH CuHs-G-O EXAMPLE 4 The preparation of 7 -hydr0xy-2-aldo-2,13-dimethyl-perhydrophenanthryl-I-acetic acid (IX) from androstane-3a-17oz-di0l-16-0ne (X) To 131 mg. of androstane 3a-17a-diol-16-one (X)is added 7.9 cc. of 0.0598 molar lead tetra'acetate in acetic acid.After the steroid has totally dissolved 2 cc. of 50 percent acetic acidis added and the composition is swirled for 30 minutes. 75 cc. of watercontaining 1 percent ethylene glycol is added with mixing, and after afew minutes the aqueous solution is extracted with 100 cc. of ethylether. The ethereal phase is separated and washed with an equal volumeof water and then evaporated in vacuum at 30 C. The aldehyde acid (IX)is secured in cryshtlalline form and may be further purified by waterwas es.

OH: OH OH: CH: CH;

O OHO C D C -OH2CO DE A B A B X IX EXAMPLE 5 The preparation of7-benzoyl-marrian0lic acid hemialdehyde (tertiary) To a solution of 25mg. of 16-keto-a-estradiol-3-benzoate (VII) in 1.5 cc. methanol is addeda solution of 40 mg. periodic acid in 23 cc. of water. After 24 hoursthe solution is diluted with several volumes of water to pre EXAMPLE 6The preparation 07-hydr0xy-2,13-dimethyl-2-formylperhydrophenanthryl-l-acetic acid 2221mg. of androstane-3 3),l7(a)-diol-l6-one is dissolved at roomtemperature with swirling :in 9.5 cc. of 0.084 molar lead tetra-acetatein acetic acid. Then 2.5 cc. of 50 percent acetic acid is added and theswirling is continued without interruption for 30 minutes. Then cc. of1% ethylene glycol solution are added. 50 cc. of water are added and themixture is chilled. After about a day at low temperature the precipitateis collected, washed well with water, and dried at room temperature. Ayield of 192 mg. of7-hydroxy-2,13-dimethy1-2-formylperhydrophenanthryl-l-acetic acid isobtained.

It will be understood that numerous changes may be made in the variousingredients, their amounts, and the conditions under which they arereacted, without departing from the spirit of the invention, especiallyas described in the following claims.

The stereochemical designations at position 17 employed in thisapplication and in the parent application Serial No. 104,378, filed July12, 1949, now Patent No. 2,615,041, dated October 21, 1952, conform tothe terminology used in Gilman, Organic Chemistry, second edition, 1943,volume II, chapter 19, John Wiley & Sons Inc., New York, N. Y., and byHuffman and Lott, I. Am. Chem. Soc., 71, 719 (1949).

I claim:

1. A compound selected from the group consisting of CH: CH;

CHO

and

CH: CH:

-OHO

a from the group consisting of CHO CHO

whighwomprises nlid ls g a StQ iQ F seleflq qm;

group; consisting-r of GE; Q H

and

013;, OH OH}.

the

with-elem tetm-alkgnoate in a, lower alkan oic acid in the pres'ncebfer, 'aiid isolating the. prb'duct? thus formed. 5. "1Tlf1e rcce off'piodiicin'g '2,l3r-dimethyl 2-formyh7-hydroxydpdechydtbphenanthrenel-acetic acid which cpgipri ses qxidiziiig'A'5z111drostene-3 (B),17(a)-diol-16- one Withlead tetra-acetate inaqueous acetic acid and isoiating the product thus formed.

6. The'pr'ocess of producing 2,13-di1nethy1-2-formy1-7-hydroxyperhydrophenanthrene-l-acetic acid which comprises oxidizingandrostane-3(a),17(a)-diol-16-one with lead tetra-acetate aqueous aceticacid and isolating the product; sq fqrmed.

No references cited.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF
 4. THE PROCESS OFPRODUCING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF